There is a well-known connection between calcium and vitamin D nutrition and bone health. However, the connection between iron and bone health is less well established. Iron deficiency has been reported to decrease BMD in animal models and in vitro studies have demonstrated that iron deficiency affects osteoblast function. Osteoblasts and osteocytes produce the hormone FGF23, which plays a critical role in phosphate and vitamin D metabolism by increasing urinary phosphate excretion and decreasing production of 1,25 dihydroxyvitamin D. Experiments from our laboratory demonstrate that low iron concentrations are associated with high levels of FGF23 in patients with autosomal dominant hypophosphatemic rickets (ADHR). Furthermore, the increase in FGF23 concentrations is correlated with disease activity in ADHR. Preliminary data indicate that plasma FGF23 concentrations, as measured by the C-terminal assay, are also inversely correlated to serum iron concentrations in normal individuals. Data in mice also indicated that low iron diets result in marked increases in Fgf23 mRNA and protein expression, but excess intact Fgf23 is cleaved between arginine 179 and serine 180 and inactive fragments are secreted. Our overarching hypotheses are 1) low serum iron concentrations increase FGF23 message and protein, much of which is cleaved before secretion; 2) low iron concentrations decrease BMD and 3) genetic polymorphisms influence iron, TIBC and ferritin concentrations. We currently have bone density measurements, completed questionnaires, serum biochemistries, blood and urine samples from over 4,000 healthy premenopausal women (aged 20-45) and men (age 20-60), who were ascertained as part of ongoing studies of the genetics of bone fragility/strength. A subset of this group (1524 premenopausal white women) has been genotyped for over 500,000 SNPs. Therefore, we propose studying these previously ascertained individuals to test the above hypotheses. Successful completion of the proposed investigations will elucidate the effect of iron status on FGF23 metabolism and bone density in normal individuals, provide an understanding of racial differences in phosphate homeostasis, and identify genetic factors affecting iron status. PUBLIC HEALTH RELEVANCE: The goals of this application are to elucidate the effect of iron status on FGF23 metabolism and bone density in normal individuals, understand racial differences in phosphate homeostasis, and to perform a genome wide association study to identify genetic factors that affect iron status.